The genetic characterization of several inherited forms of Parkinson's disease (PD) in the past decade has allowed the conduct of mechanistic studies about the molecular determinants of dopaminergic neuronal survival, the response of these neurons to endogenous and exogenous insults, and their demise in this disease. DJ-1 is one of five genes identified thus far to be linked to inherited PD. The recessive transmission of the two original mutations identified in the DJ-1 locus in affected pedigrees suggests that normal DJ-1 functions as a neuroprotective molecule in dopaminergic neurons, and that this property is lost with the disease causing mutations. This application proposes to elucidate these neuroprotective mechanisms and to address how perturbations in these processes lead to PD. The first specific aim proposes to expand on our recent discovery that wild-type DJ-1 inhibits the Daxx/ASK1 death signaling pathway, to investigate how various mutations in DJ-1 influence this apoptotic mechanism, and how the anti-oxidant function of DJ-1 relates to this pathway using cellular models. The second specific aim will address the in vivo relevance of this pathway in the brains of PD subjects and of genetically engineered mice. And the third specific aim focuses on the cytoprotective function of DJ-1 by modulating transcription of genes that are key to the survival of dopaminergic neurons both through Daxx-dependent and Daxx-independent mechanisms. The ultimate objective of these studies is to ease the Parkinson's disease burden by identifying potential targets for therapeutic interventions that can also benefit sporadic PD. For Lay public: Mutations in the DJ-1 gene is one of the causes of inherited Parkinson's disease. The goal of this project is to understand the normal functions of DJ-1 and how defects in these functions lead to nerve cell degeneration in the brain. Clarifying these events can help develop treatments that could potentially slow down or block brain cell death.